3708 J. Org. Chem., Vol. 40, No. 25,1975
Bartholomew, Dea, Robins, and Revankar
27 mg (50%) of 33, mp 132-133O. A mixture melting point of the two samples of 33 was unchanged.
Acknowledgment. This investigation was made possible through Research Grant GM 11520 of the National Institutes of Health. The support is gratefully acknowledged. Registry No.-1, 56783-59-6; 2, 40773-64-6; 3, 50272-14-5; 4, 50272-15-6; 5, 50272-16-7; 6, 50272-17-8; 7, 50272-18-9; 8, 5027219-0; 9, 50421-06-2; loa, 50272-20-3; 10 isomer A, 56783-60-9; 12, 50272-21-4; 13, 50272-22-5; 14, 50272-23-6; 15, 56783-61-0; 16, 20196-81-0; 17, 56783-62-1; 18, 56783-63-2; 19, 56783-64-3; 20, 56783-65-4; 21, 56783-66-5; 22, 56783-67-6; 23, 56783-68-7; 24, 56783-69-8; 25, 56783-70-1; 26, 56783-71-2; 28, 56783-72-3; 29, 56816-60-5; 30, 22395-75-1; 31, 56783-73-4; 32, 50272-24-7; 33, 50272-13-4; benzyl chloride, 100-44-7; methanesulfonyl chloride, 124-63-0;p-toluenesulfonyl chloride, 98-59-9;acetone, 67-64-1,
References and Notes (1) A preliminary account of pari of this work has been published: C. L. Ste-
vens, K. w. Schuitze, D. J. Smith, P. M. Piilal, P. Rubenstein, and J. L. Stromlnger, J. Am. Chem. Soc., 95, 5767 (1973). (2) 0.Luderitz, A. M. Staub, and 0. Westphal, Bacterial. Rev., 30, 192 (1966).
(3) P. Gonzalez-Porque and J. L. Strcminger, J. Biol. Chem., 247, 6748 (1972), and references cited therein. (4) For a review, see H. Nikaido and W. 2. Hassid, Adv. Carbohydr, Chem., 26, 351 (1971). (5) S. Matsuhashi, M. Matsuhashi, and J. L. Strominger, J. Bo/. Chem., 241, 4267 (1966). (6) H. Nikaido and K. Nikaido, J. Bid. Chem., 241, 1376 (1966). (7) S.Matsuhashi and J. L. Strominger, J. Bioi. Chem., 242, 3494 (1967). (8) W. Richle, E. K. Winkler, D. M. Howley, M. Dobier, and W. Keller-Schleriein, Helv. Chim. Acta, 55, 467 (1972). (9) H. Paulsen, K. Eberstein, and W. Kobernick, Tetrahedron Left.. 4377 (1974). (10) T. D. inch and G. J. Lewis, Carbohydr. Res., 15, 1 (1970). (11) E. J. Hedgley, W. G. Overend, and R. A. C. Rennie, J. Chem. Soc., 4701 (1963). (12) D. N. Jones and M. Saeed, J. Chem. Soc.. 4657 (1963). (13) E. J. Hedgley, 0. Meresz, W. G. Overend, and R. A. C. Rennie, Chem. lnd. (London), 938 (1960). (14) H. Huber and T. Reichsteln, Helv. Chim. Acta, 31, 1645 (1948). (15) W. D. Closson, P. Wriede, and S. Bank, J. Am. Chem. Soc., 88, 1581 (1966). (16) K. Kapek, J. Nemec, and J. Jary, Collect. Czech. Chem. Commun., 33, 1758 (1968). (17) 0. Westphal and S.Stirm, Justus Liebigs Ann. Chem., 620, 8 (1959). (18) K. Antonakis, Bull. Soc. Chlm. Fr., 2972 (1968). (19) K. Antonakis, private communication, 1969. (20) E. L. Albano and D. Horton, Carbohydr. Res., 11, 485 (1969). (21) P. M. Collins, P. T. Doganges, A. Kolarikoi, and W. G. Overend, Carbohydr. Res., 11, 199 (1969).
Imidazo[ 1,2-c]pyrimidine Nucleosides. Synthesis of N-Bridgehead Inosine Monophosphate and Guanosine Monophosphate Analogues Related to 3-Deazapurines’ David G. Bartholomew, Phoebe Dea, Roland K. Robins, and Ganapathi R. Revankar*
ICN Pharmaceuticals, Inc., Nucleic Acid Research Institute, Iruine, California 92664 Received June 10,1975 The first chemical syntheses of imidazo[l,2-c]pyrimidinenucleosides are described. Cyclization of 4-amino-6chloro-2-pyrimidinol (2) with bromoacetaldehyde diethyl acetal gave 7-chloroimidazo[l,2-c]pyrimidin-5-one (3). Direct glycosylation of the trimethylsilyl derivative of 3 with 2,3,5-tri-0-acetyl-D-ribofuranosyl bromide in acetonitrile gave an anomeric mixture of 7-chloro-l-(2,3,5-tri-0-acetyl~D-ribofuranosyl)imidazo[l,2-c]pyrimidin-5-one (12) which on deacetylation and separation of anomers furnished 7-chloro-l-~-D-ribofuranosylimidazo[l,2-c]pyrimidin-5-one (10) and its 01 anomer (11). However, the glycosylation of MesSi-3 with tetra-0-acetyl-P-D-ribofuranose in dichloroethane containing stannic chloride, followed by aminolysis, gave only the anomer 10. Catalytic dehalogenation of 10 and 11 furnished the 3-deazainosine analogue, l-~-D-ribofuranosylimidazo[l,2-c]pyrimidin5-one (E), and its a anomer (17), respectively. Amination of 10 gave 7-amino-l-~-D-ribofuranosylimidazo[l,2clpyrimidin-5-one (13),an analogue of 3-deazaguanosinepossessing a bridgehead nitrogen atom. Phosphorylation of 15, 17, and 13 gave l-~-D-ribofuranosylimidaao[l,2-c]pyrimidin~5-one 5’-monophosphate (16), the IMP analogue, its N anomer (18), and 7-amino-l-~-~-ribofuranosylimidazo[l,2-c]pyrimidin-5-one 5’-monophosphate (14), the GMP analogue, respectively. The assignment of site of ribosylation has been determined unequivocally by using ’”C NMR spectroscopy and the anomeric configurations have been established by using IH NMR of the 2’,3’-0-isopropylidene derivatives of 10 and 11. I t is well established that alterations of either the furanose or the base moiety of naturally occurring purine nucleosides may produce analogues that exert interesting biological effects,2 The role of the various nitrogen atoms of purine nucleosides as binding sites for important enzymes in biological systems has become the subject of considerable interest.3 The isolation of a number of antibiotics of the deazapurine series (e.g., viomycin,* tubercidin,j toyocamycine) which are isomeric or isosteric with purine are of particular interest because of their structural uniqueness and their biological proper tie^.^^,^ Since the majority of purine-type ribosides exist in the anti conformation (some exist in the syn conformation in the solid states), 3-deazapurine nucleosides deserve special attention because N3 of purine nucleosides is presumed to be involved in stabilizing the syn conformation through intramolecular hydrogen bonding [5’-OH.-N:jH].9 The syntheses of several 3-deazapurine nucleosideslO and nucleotideslOf~g~ll (A) have been
0
0
Rf
A
Rf
13 Rf = -P-D-ribofuranosyl reported. Some of these 3-deazapurine derivatives have demonstrated significant antibacterial,12 anticancer,lobVe ring and antivirall0g activity. The imidazo[l,2-~]pyrimidine system (B), which has not been explored appreciably, may be regarded as 3-deazapurine with a bridgehead nitrogen atom in which N3 and Csa are interchanged. The nucleoside analogues of imidazo[l,2-~]pyrimidine have the potential, therefore, either to emulate or t o antagonize the functions of the naturally occurring nucleosides and nucleotides.
J . Org. Chem., Vol. 40, No. 25, 1975 3709
Imidazo[l,2-~]pyrimidine Nucleosides Scheme I
]'IO
2"
3
2
1
4
1
K
AcO
JJ-2
c1
AcO
I
OAc
7
6
A&
Br
+
OAc
CH,CN
I
H
O
C
!
H
m HO
0
x0
/
Ad)
0 11
OH
10
9
HO OH 13,R, = H 14,R = pO(OH),
OAc
12
I HO
RO
H2N I R O C H X
AcO
ROC@
HO OH 15,R=H 16, R = PWOH),
These nucleoside analogues are also of particular interest since they lack an N(H) function a t position 1 of purine; hydrogen bonding of the Watson-Crick type, therefore, would not be possible. For these reasons we pursued the synthesis of 3-deaza analogues with a bridgehead nitrogen atom of some naturally occurring nucleotides, inosine monophosphate and guanosine monophosphate. The complete synthetic route consists of three parts: synthesis of an appropriate imidazo[1,2-c]pyrimidine;conversion of the starting imidazo[l,2c]pyrimidine to the required nucleoside; and finally, the phosphorylation of the nucleoside to the corresponding 5'monophosphate. The most frequently encountered procedure for the synthesis of imidazo[l,2-c]pyrimidinesinvolves the cyclization of 4(6)-aminopyrimidine derivatives with an cu-halocarbonyl compound.13 The possibility of utilizing this approach was investigated for the synthesis of 7-chloroimidazo[l,2c]pyrimidin-5(6H)-one (3). Compound 3 was particularly elected as the starting material, since the halogen group is known to deactivate its neighboring nitrogen in a glycosylation reaction14 thereby producing the requisite N1 glycosyl
17, R = H
19
18, R = PO(OH),
derivative. T h e logical key intermediate, 4-amino-6-chloro2-pyrimidinol15 (2), was prepared in 83% yield in one step from 2-methylthio-4-amino-6-pyrimidino116 (1) (Scheme I). Compound 1 was chlorinated with phosphorus oxychloride and without isolation of the intermediate, 2-methylthio-4amino-6-chloropyrimidine, the acidic aqueous solution was heated on a steam bath to obtain crystalline 2. Ring closure of 2 with bromoacetaldehyde diethyl acetal in aqueous media a t reflux gave exclusively 7-chloroimidazo[1,2-c]pyrimidin-5-one (3) in 86% yield. The assignment of this structure is based on the fact that the l H NMR (Me2SOd6-NaOD) spectrum of 3 revealed a singlet a t 6 6.46 (C8H) in addition t o two doublets at 6 7.54 (J = 2 Hz, CZH) and 7.24 (J = 2 Hz, C3H). Catalytic dehalogenation of 3 with 10%palladium on carbon in a hydrogen atmosphere readily gave imidazo[l,2-c]pyrimidin-5-one(4). The identity of this compound was confirmed by rigorous comparison of the physicocochemical data reported13e for 4,thereby confirming the structure of 3. It is of particular interest to note that earlier attempts17 to remove the chloro groups of 5substituted 2,7-dichloroimidazo[1,2-c]pyrimidines by hydrogenation were unsuccessful.
3710
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Bartholomew, Dea, Robins, and Revankar
The glycosylation of 3 was next considered. Treatment of Table I Comparison of 13C Chemical Shifts for the Anion of hexa7-Chloroimidazo[ 1,2-c]pyrimidin-S-one (C) and its methyldisilazane in the presence of ammonium sulfate, acNucleosides (10 and 11) cording to the general procedure described by WittenChemical shift, 6,ppma burg,l8 gave the trimethylsilyl derivative (7) which without further purification was treated with 2,3,5-tri-O-acetyl-DCompd c, c, c, C,b c, Cbb ribofuranosyl bromide (8) in acetonitrile a t room tempera0 ture as described previously.14J9 Under these conditions a * 3 93% yield of an anomeric mixture of 7-chloro-1-(2,3,5-tri‘**N?z 129.4 109.4 150.9 147.2 92.2 148.4 0-acetyl-D-ribofuranosyl)imidazo[ 1,2-c]pyrimidin-5-one &,; CI e (12) was obtained, which resisted our efforts to separate the pure anomers by silicic acid column chromatography. C Deacetylation of the anomeric mixture 12 with methanolic 10 118.9 111.0 155.3 148.0 89.6 144.6 11 121.3 109.9 154.7 148.2 86.2 144.6 ammonia a t ambient temperature gave 7-chloro-1-P-D-riA6C-IO 10.5 -1.6 -4.4 -0.8 2.6 3.8 bofuranosylimidazo[l,2-c]pyrimidin-5-one(10) and its a A6C-11 8.1 -0.5 -3.8 -1.0 6.0 3.8 anomer (11). The anomeric nucleosides were separated by Chemical shifts are measured from Me,SO-d,, converted fractional crystallization using methanol as the solvent; the to Me,Si scale using the relationship i 3 ~ ~ ,=s 6i M e z ~ O d+6 less soluble a anomer 11 crystallizes first, the anomeric 39.5 ppm. b Assignments tentative. ratio being almost 1:l.The purity of these nucleosides was assured by elemental analysis and by l H NMR spectroscoThe site of ribosylation was established by using l3C py. The formation of 11 is not surprising, since a number of NMR spectroscopy. The use of I3C chemical shifts for the exceptions to the Baker “trans” rule have been reported.20 determination of glycosylation site in nucleosides of fused The formation of 10 established the retainment of the 7nitrogen heterocycles has recently been d o c ~ m e n t e d The .~~ chloro group, and confirmed the directive effect of the assignments were made on the basis of the a and p substihalogen group to give exclusively the NI glycosyl derivatution shifts observed when the ribofuranosyl derivatives tive. In an effort to improve the yield of the p anomer 10 we were compared with the corresponding ionized base.26The pertinent 13C chemical shifts of the anion of 3 and its riboshave examined the use of Friedel-Crafts catalyzed glycosyylated derivatives are summarized in Table I. The assignlation procedure.’l Thus, treatment of l equiv of the triment of various carbons was obtained through examination methylsilyl derivative of 3 (7)in 1,2-dichloroethane with 1 of the multiplicity patterns in the proton-coupled spectra equiv of fully acylated ribofuranose (6) and 1.44 molar as well as comparisons of the 13C chemical shifts with relatequiv of stannic chloride afforded, after silicic acid column chromatography, a 64% yield of 7-chloro-1-(2,3,5-tri-O-ace- ed corn pound^.^^ By comparing the 13C chemical shifts of the anion of 3 (C), 10, and 11, we note that upfield shifts of tyl-~-~-ribofuranosyl)imidazo[l,2-c]pyrimidin-5-one ( 5 ) as 10.5 and 3.8 ppm were observed for C2 and cb (acarbons to light yellow foam. Nucleoside 5 was the only nucleoside N1) and a downfield shift of 1.6 ppm was observed for C3 ( p product which could be detected by TLC or column chrocarbon to N1) for the nucleoside 10; similar substitution matography procedures. Aminolysis of 5 with methanolic shifts were observed for the nucleoside 11. These changes ammonia a t ambient temperature gave an 81% yield of 10. in chemical shifts are consistent with the large upfield a Although the anomeric configuration of 10 and 11 could shifts and small downfield shifts predicted for the nucleotentatively be assigned as P and a, respectively, on the sides, which leads to the conclusion that N1 is the ribosylabasis of several empirical rules,22 and by a large negative tion site. The downfield shifts observed for the C5 and C7 specific rotation for 10 ( [ a ] 2 5 D-39.5’) and positive specific (a carbons to N6) in 10 and 11 also indicate that ribosylarotation for 11 ( [ a I z 5 D +34.07’), this could not be used for tion has not occurred a t the position. Additional supthe unequivocal assignment of anomeric configuration, port for the site of ribosylation was also obtained by the disince there are no imidazo[l,2-c]pyrimidineN1 ribosides rect comparison of the reported ultraviolet absorption available for comparison. Therefore, a more rigorous proof or the spectra of 6-methylimidazo[1,2-c]pyrimidin-5-0ne~~ was in order for this unusual heterocyclic nucleoside series. fluorescent 6-ribosylimidazo[1,2-c]pyrimidin-5-0ne~~ [A, T h e 1H NMR spectra of 10 and 11 in Me2SO-d~revealed a (0.05 N HC1) 248 s, 288, 302 nm s (t 4.4, 12.3, 7.0 X lo3); doublet (for C1rH) centered a t 6 5.85 and 6.23, respectively, (pH 7) 272, 281 s, 292 nm s ( e 11.7, 11.1, 6.7 X lo3); with a J1,2 of approximately 4.5 Hz, which contemplated , , ,X (0.05 N NaOH) 272, 281 s, 292 nm s (t 12.0, 10.9, 5.3 X the preparation of the 2‘,3’-0-isopropylidene derivative in , , ,X 1031 with the ultraviolet absorption spectra observed for 15 order to reduce the magnitude of the coupling constant to and 17 (see Experimental Section), which conclusively eswithin the acceptable limits.23 Isopropylidenation of 10 and tablished that the ribosylation has not taken place a t NG. 11 with 70% perchloric acid and 2,2-dimethoxypropane in Catalytic dehalogenation of 10 and 11 with 10% palladiacetone furnished 7-chloro-1-(2,3-0 -isopropylidene-P-Dum on carbon in a hydrogen atmosphere a t room temperaribofuranosyl)imidazo[1,2-c]pyrimidin-5-one (9) and the a ture gave the 3-deazainosine analogue 1-P-D-ribofuranosylanomer (19) in good yield. The 1H NMR spectrum of 9 in imidazo[l,2-c]pyrimidin-5-one(15) in 65% yield, and the MezSO-dG revealed a doublet centered a t 6 6.13 with a J1,2 corresponding a anomer (17) in 68% yield, respectively. of 3.5 Hz indicating the P configuration. The spectrum also Treatment of 10 with anhydrous methanol containing liqrevealed the difference between the chemical shift of the uid ammonia a t elevated temperature and pressure furtwo methyl signals of isopropylidene group to be 0.23 ppm, nished a 64% yield of 7-amino-l-~-D-ribofuranosylimidaz.~~ a difference characteristic of the (?c ~ n f i g u r a t i o nSimilar0[1,2-c]pyrimidin-5-one (13), the 3-deazaguanosine analy, the 1H NMR spectrum of 19 in Me2SO-dG revealed the logue possessing a bridgehead nitrogen atom in which N3 difference in proton chemical shifts between the isopropyliand Csa are interchanged. Typical of most of the comdene methyl groups to be almost 0.0 ppm, indicating the a pounds in the present work, 13,15, and 17 were obtained as c ~ n f i g u r a t i o n Based . ~ ~ on this data, the anomeric configuwell-defined crystalline products. Phosphorylation29 of unration for 9 and 19, and hence for 10 and 11, were unequivprotected 15 with phosphorus oxychloride using trimethyl ocally assigned as P i n d a,respectively.
7-chloroimidazo[l,2-c]pyrimidin-5(6H)-onewith
Q
Imidazo[1,2-c]lpyrimidineNucleosides
J.Org. Chem., Vol. 40, No. 25, 1975
3711
gj. The mixture was shaken under hydrogen (45 psi) at room temphosphate as siolvent a t ambient temperature provided a perature for 1.5 hr. The mixture was filtered through a Celite pad rather low yield of N-bridgehead IMP analogue, 1-P-D-riand the filtrate concentrated to 20 ml. After cooling, the crystalbofuranosylimidazo[l,2-c]pyrimidin-5-one 5'-monophosline solid was collected by filtration and dried to give 1.46 g (93%). phate (16), which was isolated in the free acid form. SimiA small sample was recrystallized from water to give pure 4: mp larly, the nucleoside 17 was phosphorylated to 1-a-D-ribo278O dec (lit.13emp 272-274O);'H NMR (MezSO-&) 6 6.63 (d, J = furanosylimidazo[l,2-c]pyrimidin-5-one 5'-monophosphate 8.0 Hz, CsH), 7.32 (d, J = 8.0 Hz, C7H), 7.45 (d, J = 2.0 Hz, C3H), 7.82 (d, J = 2.0 Hz, CzH), 11.90 (broad, NH); uv A,, (pH 1) 248 (18). Direct phosphorylation of 13 in the manner as denm s (t 5.4),282 (10.4),297 s (5.8); ,,,A (pH 7) 267 nm ( e 11.3),275 scribed above provided the GMP analogue with a bridge,,,A (pH 11) 276 nm (A X l ) , 294 s (5.7);ir head nitrogen atom, 7-amino-l-(3-D-ribofuranosylimid- s (10.0), 287 s (5.0); 1720 cm-' (C=O). azo[l,2-c]pyrinnidin-5-one 5'-monophosphate, isolated as Anal. Calcd for CsHbN30 (135.12):C, 53.33;H, 3.73;N, 31.09. the free acid after ion-exchange chromatography. T h e Found: C, 53.14;H, 3.66;N,30.96. structure of these IMP and GMP analogues was confirmed 7-Chloro-l-(2,3,5-tri-O-acetyl-D-ribofuranosyl)~midazo[ 1,2clpyrimidin-5-one (12). Methylene chloride (30 ml) saturated by 'H NMR spectra and elemental analyses. The purity with anhydrous hydrogen bromide a t -20' was added to a solution was assured by the homogeneity in several thin layer sysof 1,2,3,5-tetra-0-acetyl-&D-ribofuranose (5.7g, 17.5mmol) in dry tems and on paper electrophoresis. methylene chloride (30 ml) at -2OO. The solution was protected from moisture and allowed to warm to 0'. The excess HBr and solExperimental Section vents were removed on a rotary evaporator, and the residual syrup was coevaporated with dry toluene (3 X 50 ml). This syrupy 2,3,5Melting points were taken on a Thomas-Hoover capillary melttri-0-acetyl-D-ribofuranosyl bromide (8)was dissolved in "nanoing point apparatus and are uncorrected. Specific rotations were grade" acetonitrile30 (85ml) and added to the trimethylsilyl commeasured in a 1-dlm tube with a Perkin-Elmer Model 141 automatpound (7) obtained by refluxing 3 (2.77 g, 16.3mmol) in hexamethic digital readout polarimeter. Nuclear magnetic resonance ('H yldisilazane (HMDS, 10 ml) in the presence of a catalytic amount NMR) spectra were recorded at 60 MHz on a Hitachi Perkinof ammonium sulfate for 14 hr, under anhydrous conditions, and Elmer R-20A spectrometer in MezSO-& or DzO using DSS as an distilling off the excess HMDS in vacuo. The flask was stoppered internal standard. A Bruker HX-90 NMR spectrometer operating and stirred at room temperature for 3.5 days. The reaction mixture at 22.62 MHz in the Fourier transform mode was used to obtain was filtered to remove 0.15 g of unreacted 3. The dark filtrate was the 13C NMR spectra (20% solutions in MezSO-d6). A Fabri-Tek evaporated to dryness, and the residue was dissolved in chloroform 1074 signal averager with 4096 word memory was used for data ac(150ml), washed with saturated aqueous sodium bicarbonate solucumulation and a1 Digital PDP-8Ie computer for data processing. tion (2 X 50 ml) followed by water (2X 50 ml), and then dried over Ultraviolet spectra (uv, t X lo3, s = shoulder) were recorded on a anhydrous sodium sulfate. The chloroform was evaporated to dryCary Model 15 spectrometer and infrared spectra (ir) on a Perkinness and the residual foam was chromatographed on silica gel (400 Elmer 257 spectrophotometer (KBr pellets). Elemental analyses g) prepacked in ethyl acetate and eluted with solvent D. The band were performed by Galbraith Laboratories, Inc., Knoxville, Tenn. carrying the products was collected and evaporated to dryness, Chromatography [eolventmixtures were by volume and the systems leaving 6.15 g (93%,based on the recovery of unreacted 3) of a yelused were: D, ethyl acetate-water-1-propanol (4:2:1,upper phase); (pH l) 250 nm (e 4.3),292 s (11.7),302 (14.5), low foam: uv A,, E, ethyl acetate-ethanol-water (4:2:1);F, 2-propanol-concentrated ,,,A (pH 7) 253 nm (e 4.5),304 (16.11,313 s (14.1); 313 s (10.6); ammonium hydroxide-water (7:1:2).Evaporations were carried A,, (pH 11)253 nm (e 4.5),304 (16.1),313 s (14.1);ir 1670 (C=O out under reduced pressure with bath temperature below 30'. of heterocycle), 1750 cm-l (OAc of sugar moiety). 4-Amino-6-chloro-2-pyrimidinol(2). To a suspension of dry 'I-ChlOrO-1-(2,3,5-tri- 0-acetyl-/?-D-ribofuranosyl)imidazo[ 1f 2-methylthio-4-an~ino-6-pyrimidinol'6(1, 20.0 g, 127 mmol) in clpyrimidin-5-one (5). To a solution of 7 [prepared from 3.5 g phosphorus oxychloride (100 ml) was added with agitation N,N(20.6 mmol) of 31 in anhydrous 1,2-dichloroethane (125 ml) was diethylaniline (10 ml) and the mixture was gently refluxed for 6 hr. added 1,2,3,5-tetra-O-acetyl-~-D-ribofuranose (6, 5.6 g 20.6 mmol) The excess phosphorus oxychloride (about 65 ml) was removed in followed by stannic chloride (7.9g, 29.8 mmol). The reaction mixvacuo, and the residual syrup poured over crushed ice (200g) with ture was protected from moisture and stirred for 24 hr at ambient stirring. The cold mixture was slowly brought to room temperature temperature. The reaction solution was then poured into 120 ml of with continuous stirring, during which time nearly all insoluble saturated aqueous sodium bicarbonate solution with stirring. The material went into solution. The clear solution was decanted from resulting emulsion was filtered through Celite, and the organic a small amount of insoluble gum and was heated on a steam bath layer was washed with water (50 ml) and dried over anhydrous overnight. After refrigeration the solid that crystallized out was magnesium sulfate. The solvent was evaporated to a light brown collected to give 19.9 g of the HCl salt. The salt was dissolved in hot water (1l.), treated with charcoal, and filtered, and the hot filfoam which was chromatographed on silica gel (600 g) prepacked trate was adjusted to pH 6-7 with 40% aqueous sodium hydroxide in ethyl acetate and eluted with solvent D-ethyl acetate (1:l).The solution. After cooling the crystalline solid was collected and dried band containing the requisite product was evaporated to leave 5.6 to yield 15.4g (83%) of 2, mp >300° (lit.15mp >300°). g (64%) of light yellow foam: uv A,, (pH 1) 250 nm (e 4.3),292 s (11.8),302 (14.6),313 s (10.6);Amax (pH 7) 253 nm (e 4.6), 304 7-Chloroimidazo[ 1,2-c]pyrimidin-5-one (3). To a suspension of 4-amino-6-chloro-2-pyrimidinol (2, 19.0 g, 130 mmol) in water ,,,A (pH 11) 253 nm (C 4.6),304 (16.2), 313 s (16.2),313 s (14.1); (14.1);ir 1670 (C=O of heterocycle), 1750 cm-' (OAc). (400ml) was added bromoacetaldehyde diethyl acetal (26.0g, 132 mmol). The mixture was refluxed with stirring for 1.5hr and then 7-Chloro- l-/?-D-ribofuranosylimidazo[ l,t-c]pyrimidin-5one (10) and 7-Chloro-l-a-D-ribofuranosylimidazo[ l,2-c]pyan additional 26.0 g of bromoacetaldehyde diethyl acetal was added. Refluxing was continued until solution was complete (2-3 rimidin-6-one (11). The anomeric mixture of 7-chloro-1-(2,3,5hr). The heating mantle was replaced with an ice bath, and the tri-0-acetyl-D-ribofuranosyl)imidazo[l,2-c]pyrimidin-5-one(12, brown solution wa3 immediately neutralized with solid sodium bi6.7 g, 15.3 mmol) was dissolved in methanolic ammonia (150 ml, carbonate. The cooled mixture was filtered, and the solid was saturated at 0') and the solution was allowed to stand at room washed with cold water, then acetone, and finally with ether. The temperature overnight. The volume of the reaction solution was tan-colored solid, weighing 19.1 g (86%), was used directly without reduced to about 75 ml and the solution was kept at room temperature for 4 hr. The tan-colored solid that crystallized was collected further purification. A small sample was crystallized from water to afford an analytical sample: mp >300°; IH NMR (MezSO-&by filtration ( G ) and dried to give a chromatographically homogeNaOD) Q 6.46 (s, CsH), 7.24 (d, J = 2.0 Hz, C3H), 7.54 (d, J = 2.0 nous sample of the a anomer (111, 1.96 g (42%), mp 206-208O.Recrystallization from aqueous methanol afforded an analytically Hz, CzH); uv A,, (pH 1) 260 nm s (e 5.51,292 (12.8),304 s (7.3); pure sample: mp 209'; [aIz5D+34.07' ( c 1.0, MeZSO); IH NMR ,,,A (pH 7) 265 nm s (t 6.2), 292 (13.5); ,,,A (pH 11) 283 nm (e 12.4),301 s (7.2);ir 1680 (C=O), 3110 cm-l (NH). (MezSO-ds) 6 6.23 (d, J = 4.5 Hz, CltH), 6.86 (s, CsH), 7.77 (d, J = Anal. Calcd for (:6H&lN30 (169.57):C, 42.50;H, 2.38;N,24.78. 1.5 Hz, 2 H, CzH and C3H); uv Amax (pH 1) 250 nm s (t 4.2),289 s Found: C, 42.25;H, 2.26;N, 24.59. (13.3),299(14.9),312 s (9.8); ,,,A (pH 7) 253 nm ( t 4.2), 302 (16.4). Imidazo[ 1,2-c]pyrimidin-5-one (4).7-Chloroimidazo[l,2-c]py311 s (14.7);Amax (pH 11) 253 nm ( e 4.2),302 (16.4),311 s (14.7);ir rimidin-5-one (3, 2.0 g, 11.8 mmol) was dissolved in 50% aqueous 1645 cm-' (C=O of heterocycle). ethanol (200ml) containing concentrated ammonium hydroxide (5 Anal. Calcd for CllH12ClN30~(301.69):C, 43.79; H, 4.01, N, ml), and to this solution was added 10% palladium on carbon (0.20 13.92.Found: C, 43.40;H, 3.85;N, 13.78.
3712
J. Org. Chem., Vol. 40, No. 25,1975
Bartholomew, Dea, Robins, and Revankar
The filtrate from above ( G ) was allowed to stand in an open bea6.26(d, J = 6.5Hz, C1,H), 6.67 (d, J = 7.1Hz, CsH), 7.74(d, J ker until crystals began to form; then the container was covered 2.5 Hz, CzH), 7.85 (d, J = 2.5Hz, CZH),8.01 (d, J = 7.1Hz, CvH); and refrigerated. The crystalline solid was collected and dried to uv A,, (pH 1) 246 nm (t 4.4),283 s (10.9),292 (11.6),304 s (7.0); give 2.25 g (48%) of the P anomer (lo), mp 190-191'. An analytical A,, (pH 7) 251 nm ( t 5.5),300 (13.2);,,,A (pH 11) 251 nm ( e 5.9), sample was obtained by recrystallization from aqueous ethanol: 301 (14.5);ir 1647cm-I (C=O of heterocycle). mp 192'; [aIz5D -39.6' (c 1.0,MezSO); 'H NMR (MezS0-d~)6 Anal. Calcd for CllH13N305 (267.23):C, 49.43;H, 4.90;N, 15.73. 5.85 (d, J = 4.5Hz, CIfH),6.95(s, CsH), 7.83 (d, J = 3.0Hz, C3H), Found: C, 49.26;H, 5.14;N, 15.65. 7.98 (d, J = 3.0Hz, C2H); uv A,, (pH 1) 250 nm ( e 4.4),293 s 7-Amino-l-~-D-ribofuranosylimidazo[ 1,2-c]pyrimidin-5(14.2),301 (15.4),312 s (11.5);,,A (pH 7) 253 nm ( e 5.5), 303 one (13). A suspension of 7-chloro-l-~-D-ribofuranosylimidazo[l,2(17.1),312 s (15.7); ,,A (pH 11) 253 nm ( e 5.5),303 (17.1),312 s clpyrimidin-5-one (10, 1.5g, 49.9 mmol) in anhydrous methanol(15.7);ir 1650cm-' (C=O of heterocycle). liquid ammonia (3:1,70 ml) was heated in a sealed steel reaction Anal. Calcd for CllHlzClN305 (301.69): C, 43.79;H, 4.01,N, vessel at 100-105' for 45 hr. The resulting dark solution was evap13.92.Found: C, 43.52;H, 3.76;N, 13.78. orated to dryness and the residue was chromatographed on silica 7-Chloro-l-@-~-ribofuranosylimidazo[ 1,2-c]pyrimidin-5gel (250 g) prepacked in ethyl acetate and eluted with solvent E. one (10). A solution of 7-chloro-1-(2,3,5-tri-0-acetyl-~-D-ribofura-The band containing the requisite product was collected and evapnosyl)imidazo[l,2-c]pyrimidin-5-one(5, 3.5 g, 8.15 mmol) in orated to dryness and the residue was triturated with hot ethanol methanolic ammonia (80ml, saturated at 0') was allowed to stand (30ml) and refrigerated. The solid was collected and dried to yield at room temperature overnight. The volume was reduced to about 0.89 g (64%) of 13. A small sample was crystallized from water: mp 35 ml, and the solution was decolorized with carbon and chilled. >300° dec (sinters at 215'); [a]"D -20.4' (c 1.0,MeZSO); 'H The colorless crystals that separated were collected and dried to NMR (MezSOd6) 6 5.53 (d, J = 5.5 Hz, CIH), 5.62(9, CgH), 6.73 MezSO); uv, ir, (broad, s, NHz), 7.46 (d, J = 2.0 Hz, C3H), 7.56 (d, J = 2.0Hz, afford 1.98g (81%): mp 192'; [aIz5D-40.06' (c 1.0, and 'H NMR identical with those of 10 prepared as above. (pH 1) 265 nm (e 9.2),301 (22.1); ,,,A (pH 7)293 nm CzH); uv A,, 7-Chloro-1-(2,3- 0-isopropylidene-8-D-ribofuranosy1)im- ( t 22.6);A,, (pH 11) 292 nm ( e 22.9): ir 1635 (C=O of heterocyidazo[ 1,2-c]pyrimidin-5-one (9). 2,2-Dimethoxypropane (0.5ml) cle), 3349 cm-I ("2). and 70% perchloric acid (0.5ml) were added to dry acetone (120 Anal. Calcd for CllH14N405 (282.25):C, 46.80;H, 4.99;N, 19.85. ml). The mixture was protected from moisture and stirred at room Found: C, 46.56;H, 4.82;N, 19.60. temperature for 5 min before 7-chloro-l-~-D-ribofuranosylimida- 1-8-D-Ribofuranosylimidazo[ 1,2-c]pyrimidin-5-one 5'-Mozo[l,2-c]pyrimidin-5-one(10, 0.40g, 1.33 mmol) was added in one nophosphate (16). Freshly distilled phosphorus oxychloride (0.80 g) and trimethyl phosphate (8 ml) were cooled to 148' dec; [aIz5D-30.2' (c 1.0,HzO); 'H nished 0.28g (60%) of 19 after recrystallization from aqueous ethaNMR (D20) 6 6.17(d, J = 5.2Hz, ClrH),7.24(d, J = 8.0Hz, CsH), nol as needles: mp 202'; [oiIz5D-45.8' (c 1.0,Me2SO); 'H NMR 8.00 (d, J zz 8.0Hz, CvH), 8.13(d, J = 1.8 Hz, CsH), 8.21(d, J = (Me2SO-ds) 6 1.28 (s, 6 H of 2 CH3, J = 0.0 Hz), 6.34(d, J = 5.1 1.8Hz, C2H); uv A, (pH 1) 244 nm ( e 2.91,292 (7.8),305 s (4.8); Hz, CiIH), 6.87 (9, CaH), 7.72(d, J = 2.3 Hz, C3H), 7.78 (d, J = 2.3 ,A, (pH 7) 249 nm ( e 4.2),300 (8.7); ,,,A (pH 11) 249 nm (e 3.6), Hz, CpH); uv A,, (pH 1) 249 nm (t 4.41, 292 s (13.51,301 300 (9.9),309 s (8.7). ,,A (pH 7) 252 nm ( e 6.3),303 (17.41,312 s (15.5),313 s (10.7); Anal. Calcd for CllH14N308P (347.22):C, 38.04;H, 4.07;N, (15.7);A,,,i(pH 11) 252 nm ( e 5.3),303 (168,312s (15.3). Anal. Calcd for C ~ ~ H ~ & ~ N ~ O ~(-35 O0..7~5)H :C, Z 47.93; O H, 4.88; 12.10.Found: C, 37.74;H, 4.11;N,11.90. 1-cr-~-Ribofuranosylimidazo[1,2-c]pyrimidin-5-one &MoN, 11.98.Found: C, 48.17;H, 4.45;N, 11.99. nophosphate (18). l-a-~-Ribofuranosylimidazo[l,2-c]pyrimidinl-~-~-Ribofuranosylimidazo[ 1,2-c]pyrimidin-5-one (15). 75-one (17, 0.79,2.95mmol) was phosphorylated with phosphorus Chloro-l-~-D-ribofuranosylimidazo[l,2-c]pyrimidin-5-one (10, 1.6 oxychloride (0.9g) using trimethyl phosphate (9.5ml) as the solg, 5.32mmol) was dissolved in 50% aqueous ethanol (120ml) convent. It was treated as described in 16 to yield 0.125g (12.2%) of taining a few drops of concentrated ammonium hydroxide. To this 18: mp >183' dec; +17.2' (c 1.0,H2O); lH NMR (DzO) 6 solution was added 10% palladium on carbon (0.40g) and the mix6.51(d, J = 6.0 Hz, ClrH), 7.10 (d, J = 8.0 Hz, CaH), 7.92 (d, J = ture was hydrogenated at 40 psi at room temperature for 1 hr. The 8.0Hz,CvH), 8.01 (d, J = 2.5 Hz, C3H), 8.09 (d, J = 2.5 Hz, CzH); mixture was filtered through a Celite pad and washed with hot uv ,A,, (pH 1) 244 nm (e 3.2 ), 291 (7.81,305 s (4.5); A,, (pH 7) water (2 x 10 ml). The combined filtrate and washings were con250 nm (e 3.9),297 (8.9);,,A (pH 11) 250 nm ( e 3.9),298 (9.7),310 centrated to about 20 ml in vacuo. The white crystalline solid that s (8.9). separated was collected and dried to yield 0.92g (65%) of 15. It was Anal. Calcd for C ~ ~ H ~ ~ N ~ O(~ 365 P.2-3H ):C, ZO 36.17;H,4.41;N, recrystallized from ethanol as colorless needles: mp 196-197'; 11.50.Found C, 35.80;H, 4.30;N, 11.12. [a]ZA~-52.4' (c 1.0,MeZSO); 'H NMR (MezS0-d~)6 5.86 (d, J = 7-Amino- 1-@-D-ribofuranosylimidazo[ 1.2- clpyrimidin-55.2 Hz, CIJH),6.73(d, J = 6.1Hz, CsH), 7.84(d, J = 3.0 Hz, C3H), one 5'-Monophosphate (14). Redistilled phosphorus oxychloride 7.98 (d, J = 3.0Hz, CzH), 8.05(d, J = 6.1Hz, CvH); uv Amax (pH 1) (0.80g) and trimethyl phosphate (8ml) were cooled to 169O dec. T h i s was slightly impure, so 0.17 g o f t h i s p r o d u c t was passed t h r o u g h a c o l u m n containing t h e same resin as above (15 m l ) , t o give 0.11 g o f p u r e (14)after w o r k - u p as above: mp >172O dec; [aIz5n-62.9O (c 1.0,HzO);'H NMR (DzO) 6 5.71 (d, J = 5.5 Hz, CxfH), '7.50(s,2H,C2H a n d CsH); uv A,, (pH 1)265 nm ( t 8.4),302 (19.4); ,,,A ( p H 7) 293 nm ( 6 19.9); ,,,A (pH 11) 292
nm (c 20.3). Anal. Calcd f o r
CllH15N408P.1.5H20(389.25):C,33.94;H,4.66;
N,14.39.Found: C,34.14;H,4.38;N,14.54. Acknowledgment. The authors wish to thank Dr. Mason G . Stout for helpful discussions relative to this work. R e g i s t r y No.-l, 1074-41-5;2, 3289-35-8;3, 56817-09-5;4, 55662-66-3; 5, 56817-10-8; 6, 13035-61-5; 7, 56817-11-9; 9, 5681712-0; 10, 56817,.13-1;11, 56817-14-2;@-12, 56817-10-8;CU-12, 56817-15-3;13, 56817-16-4;14, 56817-17-5;15, 56817-18-6;16, 56817-19-7;17, !j6817-20-0;18, 56817-21-1;19, 56817-22-2;2,2dimethoxypropane, 77-76-9; phosphorus oxychloride, 10025-87-3; 7-chloroimidazo[ 1,2-c]pyrimidin-5-0ne anion, 56817-23-3.
References and Notes ( 1 ) Part of this material was presented at the 170th National Meeting of the American Chernlcal Society, Chicago, Ill., August 1975, Abstract MEDI55. (2) (a) J. A. Montgomery and H. J. Thomas, Adv. Carbohydr. Chem., 17, 301 (1962); (b) S. S. Cohen, Prog. Nucl. AcM Res. Mol. 6/01.,5, 1 (1966);(c) J. A. Montgomery, P~oQ.Med. Chem., 7 , 6 9 (1970). (3) (a) P. C. Zamecnlk, Biochem. J., 85, 257 (1962); (b) C. Woenckhaus and G. Pfleldereir, Biochem. Z.,341, 495 (1965). (4) J. H. Bowle, A. W. Johnson, and G. Thomas, Tetrahedron Lett., 863 ( 1964).
(5) (a) K. Anzai, G Nakamura, and S. Suzuki, J. Antibiot., Ser. A, 10, 201 (1957); (b) Y. Mizuno, M. Ikehara, K. A. Watanabe, S. Suzukl, and T. Itoh, J. Org. Chlsm., 28, 3329 (1963). (6) (a) N. H. Nlshlmura, K. Katagirl, K. Sato, M. Mayama, and N. Shlmaoka, J. Antibiot., Se,: A, 9, 343 (1961); (b) E. C. Taylor and R. W. Henkes, J. Am. Chem. Soa., 87, 1995 (1965). (7) R. K. Robins, L. B. Townsend, F. Cassldy, J. F. Garster, A. F. Lewis, and A . L. Miller, J. Neterocycl. Chem., 3, 110 (1986). (8) S.S. Tavaie and H. M. Sobeli, J. Mol. Blob, 48, 109 (1970). (9) W. Saenger, Arigew. Chem., Int. Ed. Engl., 12, 591 (1973). (10) (a) Y. Mlzuno, 7'.Itoh, and K. Saito, J. Org. Chem., 29, 2611 (1964); (b) J. A. Montgomery and K. Hewson, J. Med. Chem., 9, 105 (1966); (c) R. J. Rousseau, L. B. Townsend, and R. K. Robins, B&hem/stry, 5, 756
3713
(1966); (d) Y. Mizuno, S. Tazawa, and K. Kageura, Chem. Pharm. Bull,, 16, 2011 (1968); (e) J. A. May, Jr., and L. B. Townsend, J. Chem. SOC., Perkln Trans. 1, 125 (1975);(f) P. D. Cook, R. J. Rousseau, A. M. Mian, R. B. Meyer, Jr., P Dea, G. kanovics, D. G. Streeter, J. T. Witkowskl, M. G. Stout, L. N. Simon, R. W. Sldwell, and R. K. Robins, J. Am. Chem. Soc., 97, 2916 (1975); (9) P. D. Cook, R. J. Rousseau, A. M. Mian, P. Dea, J. T. Witkowski, and R. K. Robins, ibid., in press. ( 1 1 ) M. Ikehara, T. Fukui, and S.Uesugi, J. Biuchem., 76, 107 (1974). (12) K. B. deRoos and C. A. Salemink, Recl. Trav. Chim. Pays-Bas, 90, 1166
(1971). (13) (a) G. R. Ramage and G. Trappe, J. Chem. SOC.,4410 (1952); (b) R. H. Martin and J. Mathieu, Tetrahedron, 1, 75 (1957); (c) C. W. Noell and R. K. Robins, J. Heterocycl. Chem.. 1, 34 (1964); (d) K. L. Nagpal and M. M. Dhar, Tetrahedron, 23, 1297 (1967); (e) M. Yanai, S. Takeda, T. Baba, and K. Kitagawa, J. Pharm. SOC.Jpn., 94, 1503 (1974). (14) G. R. Revankar, R. K. Robins, and R. L. Tolman, J. Org. Chem., 39,
1256 (1974). (15) (a) M. Israel, H. K. Protopapa, H. N. Schiein, and E. J. Modest, J. Med. Chem., 7, 5 (1964);(b) Y. Nltta, K. Okui, and K. Ito, Chem. Pharm. Bull,, 13, 557 (1965). (16) B. R. Baker, J. P. Joseph, and R. E. Schaub, J. Org. Chem., 19, 631 (1954). (17) C. L. Schmldt and L. B. Townsend, J. Heterocycl. Chem., 7, 715 (1970). (18) E. Wittenburg, 2.Chem., 4, 303 (1964). (19) G. R. Revankar and R. K. Robins, Ann. N.Y. Acad. Scl., 255, 166 (1975). (20) The formation of a small amount of pyrimidine a-nucleoside was reported In rather severe conditlons employed In the fusion of MesSi-pyrlmldine derivative wlth trl-O-benzoyl-D-ribofuranosyl chloride [see (a) T. Nishimura, B. Shimizu, and I. Iwal, Chem. Pharm. Bull., 12, 1471 (1964); (b) G. L. Szekeres and T. J. Bardos, J. Med. Chem., 13, 708 (1970)] and sliyl alkylation procedure employing purine analogs [see (c) C. L. Schmidt, W. J. Rusho, and L. B. Townsend, Chem. Commun., 1515 (1971);(d) J. A. Montgomery and K. Hewson, ibld., 15 (1969)l. (21) U. Niedbaila and H. VorbrUggen, Angew. Chem., lnt. Ed. Engl,, 0, 461
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Pyrimido[4,5- b][l,l]oxazines, 8-Oxadihydropteridined Danny L. Dunn and Charles G. Skinner" Department of Chemistry, North Texas State University, Denton, Texas 76203 Received May 16,1975 T h e synthesis a n d characterization of several 2-amino-4-hydroxy-6- and/or -7-(substituted)pyrimido[4,5-b][1,4]oxazines (8-oxadihydropteridines)have been accomplished. These compounds are homeosteric analogues o f t h e 7,13-dihydropteridine m o i e t y a n d were produced by t h e condensation of 2,5-diamino-4,6-pyrimidinediol and a n cu-halo ketone. Hydrogenation o f the N5-C6 double b o n d in formic acid produced a m i x t u r e o f cis a n d trans isomers when b o t h t h e 6 a n d 7 positions were substituted. An analysis of t h e i r NMR spectra indicated a preference f o r cis isomer formation.
Homeosteric2replacement of the NSnitrogen in the pterthe reaction of an a-halo ketone and 2,4,Q-triamino-6-pyriidine nucleus by oxygen has not been widely studied. Howmidinol to yield 2,4-diamino-8-oxadihydropteridine derivaever, synthesis of the pyrimido[4,5-6][1,4]oxazine (8-oxative.6 Unfortunately, this method often yielded a pteridine dihydropteridine) ring system has been accomplished by as the major product in preference to a 8-oxadihydroptericyclization of 5-(chloroacetamido)-4-methyl-2,6-pyrimi- dine derivative. A synthesis of the 8-oxadihydropteridine dinediol t o give 2,6-dihydroxy-4-methyl-8-oxadihydropter- ring system was then attempted by the condensation of an i d i r ~ e .More ~ ? ~ recently, another route has been reported by a-halo ketone and 2,5-diamino-4,6-pyrimidinediol.' In con-
